Cancer remains a major cause of death in the U.S. and worldwide. The cancer vaccine market is growing rapidly. Lymphoma vaccines account for about 0.5% of the market. Effective tumor vaccines may be useful to prevent tumor growth and/or may be useful as being a more effective, less toxic alternative to standard treatments for patients with advanced cancers. An antigen associated with cancer and therefore, a target for anti-tumor vaccines is WT1.
Wilm's tumor suppressor gene 1 (WT1) was identified as a cause of an embryonic malignancy of the kidney, affecting around 1 in 10,000 infants. It occurs in both sporadic and hereditary forms. Inactivation of WT1 leads to the development of Wilm's tumour, and Denys-Drash syndrome (DDS). The result is both a nephropathy as well as possible genital abnormalities. The WT1 protein has been found to interact with a host of cellular factors, including the major tumor regulator gene p53, which is also a tumor suppressor transcription factor.
WT1 is expressed in many tumor types and has been more broadly implicated in many cancers. For example, WT1 protein is localized in the cell nuclei of 75% of mesotheliomas (14,200 cases annually worldwide, with the highest incidence in the US) and in 93% of ovarian serous carcinomas (190,000 ovarian cancer cases worldwide in 2010). Additionally, WT1 has been implicated in pancreatic cancers, leukemia, lung cancer, breast cancer, colon cancer, glioblastoma, head and neck cancer as well as in benign mesothelium and cervical and ovarian cancer among others. WT1 is a target for gene therapy or immune therapy as an approach to cancer treatment.
WT1 encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system. It is, however, more dispensible in adults, thus suggesting it as a target for immune therapy. Multiple transcript variants, resulting from alternative splicing at two coding exons, have been well characterized. Use of the entire reading frame to maximize CTL coverage would be considered an advantage.
Due to the conservation of the WT1 antigen, most attempts to generate strong immunity against this gene target have not been successful. Vaccines have been previously investigated using DNA vaccine technology, pox-viral vaccine technology, Adenoviral vaccine technology, peptide vaccine technology and protein based vaccine technology. The vaccines that were investigated used the true, gene structure i.e., the native, “normal” gene. Only low level or nonfunctional T cell immunity was achieved in these investigations.
There are a few major issues with development of a more effective WT1 immunogen. Due to the similarity of the WT1 antigen to host WT1, a strong suppressor T cell response is generated, thereby blocking immune induction. In addition, the gene itself is significantly processed at the RNA level so that multiple cleaved transcripts are generated of unknown and possibly competing value. Furthermore, expression of the delivered WT1 is low, resulting in poor immunity.
Vaccines for the treatment and prevention of cancer are of great interest. Existing vaccines targeting WT1 are limited by poor antigen expression in vivo. Accordingly, a need remains in the art for the development of safe and effective vaccines that are applicable to tumors expressing WT1, thereby providing treatment of and promoting survival of such cancers.